Description: Homo sapiens leucine-rich repeat kinase 2 (LRRK2), mRNA. RefSeq Summary (NM_198578): This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8. [provided by RefSeq, Jul 2008]. Transcript (Including UTRs) Position: hg19 chr12:40,618,813-40,763,086 Size: 144,274 Total Exon Count: 51 Strand: + Coding Region Position: hg19 chr12:40,618,934-40,761,567 Size: 142,634 Coding Exon Count: 51
ID:LRRK2_HUMAN DESCRIPTION: RecName: Full=Leucine-rich repeat serine/threonine-protein kinase 2; EC=2.7.11.1; AltName: Full=Dardarin; FUNCTION: May play a role in the phosphorylation of proteins central to Parkinson disease. Phosphorylates PRDX3. May also have GTPase activity. Positively regulates autophagy through a calcium- dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. SUBUNIT: Interacts with PARK2. Interacts with PRDX3. Interacts with TPCN2. INTERACTION: O75581:LRP6; NbExp=3; IntAct=EBI-5323863, EBI-910915; Q13469:NFATC2; NbExp=3; IntAct=EBI-5323863, EBI-716258; O60260:PARK2; NbExp=3; IntAct=EBI-5323863, EBI-716346; SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane protein. Mitochondrion. Note=Localized in the cytoplasm and associated with cellular membrane structures. Associates with the mitochondrial outer membrane. TISSUE SPECIFICITY: Expressed throughout the adult brain, but at a lower level than in heart and liver. Also expressed in placenta, lung, skeletal muscle, kidney and pancreas. In the brain, expressed in the cerebellum, cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, temporal lobe and putamen. Expression is particularly high in brain dopaminoceptive areas. DISEASE: Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:607060]. A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients. SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. SIMILARITY: Contains 12 LRR (leucine-rich) repeats. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 Roc domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/LRRK2";
Alzheimer's disease; Parkinson's disease; progressive supranuclear palsy; dementia, frontotemporal; multiple system atropy Hernandez, D. et al. 2005, The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other NEUROLOGICALenerative diseases., Neuroscience letters. 2005 Dec;389(3):137-9.
[PubMed 16102903]
Crohn's disease Barrett ,et al. 2008, Genome-wide assocation defines more than 30 distinct susceptibility loci for Crohn's disease, Nature genetics 2008 40- 8 : 955-62.
[PubMed 18587394]
essential tremor Deng, H. et al. 2006, The LRRK2 I2012T, G2019S and I2020T mutations are not common in patients with essential tremor, Neurosci Lett 2006.
[PubMed 16939701]
LRKK2 I2012T, G2019S and I2020T variants are rare causes of Caucasian ET.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q5S007
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000165 MAPK cascade GO:0000186 activation of MAPKK activity GO:0000187 activation of MAPK activity GO:0001933 negative regulation of protein phosphorylation GO:0001934 positive regulation of protein phosphorylation GO:0006468 protein phosphorylation GO:0006897 endocytosis GO:0006914 autophagy GO:0006979 response to oxidative stress GO:0007005 mitochondrion organization GO:0007030 Golgi organization GO:0007040 lysosome organization GO:0007283 spermatogenesis GO:0007528 neuromuscular junction development GO:0008340 determination of adult lifespan GO:0009267 cellular response to starvation GO:0010468 regulation of gene expression GO:0010506 regulation of autophagy GO:0010508 positive regulation of autophagy GO:0010738 regulation of protein kinase A signaling GO:0010955 negative regulation of protein processing GO:0010977 negative regulation of neuron projection development GO:0014041 regulation of neuron maturation GO:0016242 negative regulation of macroautophagy GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0019722 calcium-mediated signaling GO:0021756 striatum development GO:0021772 olfactory bulb development GO:0022028 tangential migration from the subventricular zone to the olfactory bulb GO:0030154 cell differentiation GO:0031398 positive regulation of protein ubiquitination GO:0032091 negative regulation of protein binding GO:0032092 positive regulation of protein binding GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process GO:0033160 positive regulation of protein import into nucleus, translocation GO:0034260 negative regulation of GTPase activity GO:0034599 cellular response to oxidative stress GO:0034613 cellular protein localization GO:0035556 intracellular signal transduction GO:0035564 regulation of kidney size GO:0035640 exploration behavior GO:0035641 locomotory exploration behavior GO:0035751 regulation of lysosomal lumen pH GO:0040012 regulation of locomotion GO:0042391 regulation of membrane potential GO:0043068 positive regulation of programmed cell death GO:0043406 positive regulation of MAP kinase activity GO:0043547 positive regulation of GTPase activity GO:0046039 GTP metabolic process GO:0046777 protein autophosphorylation GO:0048312 intracellular distribution of mitochondria GO:0048812 neuron projection morphogenesis GO:0051646 mitochondrion localization GO:0051770 positive regulation of nitric-oxide synthase biosynthetic process GO:0051900 regulation of mitochondrial depolarization GO:0051966 regulation of synaptic transmission, glutamatergic GO:0060070 canonical Wnt signaling pathway GO:0060079 excitatory postsynaptic potential GO:0060159 regulation of dopamine receptor signaling pathway GO:0060161 positive regulation of dopamine receptor signaling pathway GO:0060828 regulation of canonical Wnt signaling pathway GO:0061001 regulation of dendritic spine morphogenesis GO:0070585 protein localization to mitochondrion GO:0070997 neuron death GO:0071287 cellular response to manganese ion GO:0071407 cellular response to organic cyclic compound GO:0072593 reactive oxygen species metabolic process GO:0090140 regulation of mitochondrial fission GO:0090263 positive regulation of canonical Wnt signaling pathway GO:0090394 negative regulation of excitatory postsynaptic potential GO:1900244 positive regulation of synaptic vesicle endocytosis GO:1901214 regulation of neuron death GO:1901215 negative regulation of neuron death GO:1901727 positive regulation of histone deacetylase activity GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway GO:1902499 positive regulation of protein autoubiquitination GO:1902692 regulation of neuroblast proliferation GO:1902803 regulation of synaptic vesicle transport GO:1902823 negative regulation of late endosome to lysosome transport GO:1902902 negative regulation of autophagosome assembly GO:1903125 negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation GO:1903206 negative regulation of hydrogen peroxide-induced cell death GO:1903215 negative regulation of protein targeting to mitochondrion GO:1903217 negative regulation of protein processing involved in protein targeting to mitochondrion GO:1903351 cellular response to dopamine GO:1903980 positive regulation of microglial cell activation GO:1904469 positive regulation of tumor necrosis factor secretion GO:1904887 Wnt signalosome assembly GO:1905279 regulation of retrograde transport, endosome to Golgi GO:1905289 regulation of CAMKK-AMPK signaling cascade GO:2000172 regulation of branching morphogenesis of a nerve GO:2000300 regulation of synaptic vesicle exocytosis
JA482232 - Sequence 215 from Patent WO2011072091. JE980524 - Sequence 215 from Patent EP2862929. LP895247 - Sequence 111 from Patent EP3253886. BC117180 - Homo sapiens leucine-rich repeat kinase 2, mRNA (cDNA clone MGC:150789 IMAGE:40125731), complete cds. AY792511 - Homo sapiens leucine-rich repeat kinase 2 (LRRK2) mRNA, complete cds. AK127729 - Homo sapiens cDNA FLJ45829 fis, clone NT2RP8006452. JA537589 - Sequence 101 from Patent WO2011114106. JA537591 - Sequence 103 from Patent WO2011114106. AL832453 - Homo sapiens mRNA; cDNA DKFZp451G151 (from clone DKFZp451G151). JD500098 - Sequence 481122 from Patent EP1572962. JD261655 - Sequence 242679 from Patent EP1572962. JD048742 - Sequence 29766 from Patent EP1572962. JD288374 - Sequence 269398 from Patent EP1572962. JD291666 - Sequence 272690 from Patent EP1572962. JD081768 - Sequence 62792 from Patent EP1572962. AK131537 - Homo sapiens cDNA FLJ16769 fis, clone BRAWH3022866. AK122640 - Homo sapiens cDNA FLJ16068 fis, clone HLUNG2000751, weakly similar to MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 9 (EC 2.7.1.-). JA537590 - Sequence 102 from Patent WO2011114106. AL834529 - Homo sapiens mRNA; cDNA DKFZp434H2111 (from clone DKFZp434H2111). BX640975 - Homo sapiens mRNA; cDNA DKFZp686E15222 (from clone DKFZp686E15222). AK026776 - Homo sapiens cDNA: FLJ23123 fis, clone LNG08039. JD311251 - Sequence 292275 from Patent EP1572962. JD110061 - Sequence 91085 from Patent EP1572962. JD314919 - Sequence 295943 from Patent EP1572962. JD039830 - Sequence 20854 from Patent EP1572962. JD392429 - Sequence 373453 from Patent EP1572962. JD297058 - Sequence 278082 from Patent EP1572962. JD519931 - Sequence 500955 from Patent EP1572962. JD237895 - Sequence 218919 from Patent EP1572962.
Biochemical and Signaling Pathways
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa05012 - Parkinson's disease
Reactome (by CSHL, EBI, and GO)
Protein Q5S007 (Reactome details) participates in the following event(s):
R-HSA-8857565 Phosphorylated GPNMB recruits PTK6 and LRRK2 in the presence of LINC01139 R-HSA-8857577 LINC01139 facilitates PTK6 autophosphorylation R-HSA-8857583 LINC01139 promotes phosphorylation of HIF1A by PTK6 and LRRK2 R-HSA-8857538 PTK6 promotes HIF1A stabilization R-HSA-8848021 Signaling by PTK6 R-HSA-9006927 Signaling by Non-Receptor Tyrosine Kinases R-HSA-162582 Signal Transduction